Dyrk1A-ASF-CaMKIIδ Signaling Is Involved in Valsartan Inhibition of Cardiac Hypertrophy in Renovascular Hypertensive Rats

Abstract

Objectives: It is known that the expression, activity and alternative splicing of Ca²⁺/calmodulin-dependent protein kinase IIδ (CaMKIIδ) are dysregulated in the cardiac remodeling process. Recently, we found a further signaling pathway, by which dual-specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1A) regulates the alternative splicing of CaMKIIδ via the alternative splicing factor (ASF), i.e. Dyrk1A-ASF-CaMKIIδ. In this study, we aimed to investigate whether Dyrk1A-ASF-CaMKIIδ signaling was involved in valsartan inhibition of cardiac hypertrophy in renovascular hypertensive rats. Methods: Rats were subjected to two kidney-one clip (2K1C) surgery and then treated with valsartan (30 mg/kg/day) for 8 weeks. Hypertrophic parameter analysis was then performed. Western blot analysis was used to determine the protein expression of Dyrk1A and ASF and RT-PCR was used to analyze the alternative splicing of CaMKIIδ in the left ventricular (LV) sample. Results: Valsartan attenuated cardiac hypertrophy in 2K1C rats but without impairment of cardiac systolic function. Increased protein expression of Dyrk1A and decreased protein expression of ASF were observed in the LV sample of 2K1C rats. Treatment of 2K1C rats with valsartan reversed the changes in Dyrk1A and ASF expression in the LV sample. Valsartan adjusted the 2K1C-induced imbalance in alternative splicing of CaMKIIδ by upregulating the mRNA expression of CaMKIIδC and downregulating the mRNA expression of CaMKIIδA and CaMKIIδB. Conclusions: Valsartan inhibition of cardiac hypertrophy in renovascular hypertensive rats was mediated, at least partly, by Dyrk1A-ASF-CaMKIIδ signaling.

Dyrk1A-ASF-CaMKIIδ Signaling: New Mechanistic Insight Involved in Valsartan Inhibition of Cardiac Hypertrophy?

“…More importantly, valsartan tuned the 2K1C-induced imbalance in the alternative splicing of CaMKIIδ by upregulating the expression of CaMKIIδC and downregulating the expression profiles of CaMKIIδA and CaMKIIδB. This study by Yao et al [10] is the first to suggest that valsartan attenuates cardiac hypertrophy in renovascular hypertensive rats through Dyrk1A-ASF-alternative splicing of the CaMKIIδ signaling pathway. However, to further confirm this signaling cascade, Dyrk1A inhibitors should be utilized in the valsartan-treated 2K1C rats in future studies.…”

“…Recently, in an elegant study, Yao et al [10 ]reported a new signaling pathway, Dyrk1A (dual-specificity tyrosine phosphorylation-regulated kinase 1A)-ASF (alternative splicing factor)-CaMKIIδ (Ca 2+ /calmodulin-dependent protein kinase II delta), which is also involved in ARB treatment for cardiac hypertrophy (fig. 1).…”

RIPK3‐Mediated Necroptosis in Diabetic Cardiomyopathy Requires CaMKII Activation

“…Alternative splicing of CaMKII δ is strictly regulated. Once it is disordered, the expression of three variants imbalances to lead to cardiomyocyte dysfunction and ultimately heart diseases [ 22 ].…”

Ca2+/Calmodulin-Dependent Protein Kinase II Regulation by Inhibitor 1 of Protein Phosphatase 1 Protects Against Myocardial Ischemia–Reperfusion Injury

“…Previous research found that CaMKII activation was closely related to its subcellular localization, subtypes, and splicing variants. 15 Moreover, after alternative splicing, CaMKIIdA, CaMKIIdB, and CaMKIIdC are produced. 16 Protein phosphatase 1 (PP1) is a multifunctional phosphatase, which decreases the phosphorylation of splicing factors to regulate alternative splicing of CaMKIId.…”

“…Previous research found that CaMKII activation was closely related to its subcellular localization, subtypes, and splicing variants. 15 Moreover, after alternative splicing, CaMKIIδA, CaMKIIδB, and CaMKIIδC are produced. 16…”